bims-tumime 2024-06-02 papers

Issue of 2024–06–02
four papers selected by
Alex Muir, University of Chicago

bioRxiv. 2024 May 14. pii: 2024.05.11.593633. [Epub ahead of print]

Temporal Single Cell Analysis of Leukemia Microenvironment Identifies Taurine-Taurine Transporter Axis as a Key Regulator of Myeloid Leukemia.

Benjamin J Rodems, Sonali Sharma, Cameron D Baker, Christina M Kaszuba, Takashi Ito, Jane L Liesveld, Laura M Calvi, Michael W Becker, Craig T Jordan, John M Ashton, Jeevisha Bajaj.

Signals from the microenvironment are known to be critical for development, sustaining adult stem cells, and for oncogenic progression. While candidate niche-driven signals that can promote cancer progression have been identified 1-6 , concerted efforts to comprehensively map microenvironmental ligands for cancer stem cell specific surface receptors have been lacking. Here, we use temporal single cell RNA-sequencing to identify molecular cues from the bone marrow stromal niche that engage leukemia stem cells (LSC) during oncogenic progression. We integrate these data with our RNA-seq analysis of human LSCs from distinct aggressive myeloid cancer subtypes and our CRISPR based in vivo LSC dependency map 7 to develop a temporal receptor-ligand interactome essential for disease progression. These analyses identify the taurine transporter (TauT)-taurine axis as a critical dependency of myeloid malignancies. We show that taurine production is restricted to the osteolineage population during cancer initiation and expansion. Inhibiting taurine synthesis in osteolineage cells impairs LSC growth and survival. Our experiments with the TauT genetic loss of function murine model indicate that its loss significantly impairs the progression of aggressive myeloid leukemias in vivo by downregulating glycolysis. Further, TauT inhibition using a small molecule strongly impairs the growth and survival of patient derived myeloid leukemia cells. Finally, we show that TauT inhibition can synergize with the clinically approved oxidative phosphorylation inhibitor venetoclax 8, 9 to block the growth of primary human leukemia cells. Given that aggressive myeloid leukemias continue to be refractory to current therapies and have poor prognosis, our work indicates targeting the taurine transporter may be of therapeutic significance. Collectively, our data establishes a temporal landscape of stromal signals during cancer progression and identifies taurine-taurine transporter signaling as an important new regulator of myeloid malignancies.

DOI: https://doi.org/10.1101/2024.05.11.593633

Acta Pharmacol Sin. 2024 May 29.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Xiao-Hui Liang, Xin-Yi Chen, Yue Yan, Ao-Yu Cheng, Jia-Yi Lin, Yi-Xin Jiang, Hong-Zhuan Chen, Jin-Mei Jin, Xin Luan.

Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Keywords: dynamic interplay; immune response; metabolic reprogramming; targeted strategies; tumor microenvironment

DOI: https://doi.org/10.1038/s41401-024-01304-w

Trends Cancer. 2024 May 30. pii: S2405-8033(24)00096-7. [Epub ahead of print]

COX2-dependent suppression of anticancer immunity.

María Cecilia Lira, Lorenzo Galluzzi, Claire Vanpouille-Box.

Prostaglandin E2 (PGE2) is well known to promote tumor progression by boosting cancer cell proliferation while inhibiting anticancer immunity. Recent data from Lacher et al. and Morotti et al. demonstrate that one of the mechanisms through which PGE2 suppresses tumor-targeting immune responses involves downregulation of interleukin 2 (IL2) receptors and consequent inhibition of mitochondrial metabolism in T cells.

Keywords: CASP3; NK cells; PTGER2; apoptosis; radiation therapy; tumor-infiltrating lymphocyte

DOI: https://doi.org/10.1016/j.trecan.2024.05.006

JCI Insight. 2024 May 30. pii: e174329. [Epub ahead of print]

Drug screening in human physiologic medium identifies uric acid as an inhibitor of rigosertib efficacy.

Vipin Rawat, Patrick DeLear, Prarthana Prashanth, Mete Emir Ozgurses, Anteneh Tebeje, Philippa A Burns, Kelly O Conger, Christopher Solís, Yasir Hasnain, Anna Novikova, Jennifer E Endress, Paloma González-Sánchez, Wentao Dong, Greg Stephanopoulos, Gina M DeNicola, Isaac Harris, David Sept, Frank M Mason, Jonathan L Coloff.

The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism end product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. These results demonstrate the broad and dramatic effects nutrient levels can have on drug response, and how incorporation of human-specific physiological nutrient media might help to identify compounds whose efficacy could be impacted in humans.

Keywords: Cancer; Cell biology; Cytoskeleton; Drug screens; Oncology

DOI: https://doi.org/10.1172/jci.insight.174329